Researchers have set their sights on macrophage activation syndrome, pathways identified in renal cells, and mechanistic target of rapamycin.
References1. Borgia RE, Gerstein M, Levy DM, et al. Features, treatment, and outcomes of macrophage activation syndrome in childhoodâonset systemic lupus erythematosus. Arthritis Rheumatol. 2018;70:616-624. doi: 10.1002/art.40417.2. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Accelerating Medicines Partnership (AMP). Accessed May 22, 2018.3. Kato H, Perl A. Blockade of Treg cell differentiation and function by the interleukin-21-mechanistic target of rapamycin axis via suppression of autophagy in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2018;70:427-438. doi: 10.1002/art.40380.
Three new studies in systemic lupus erythematosus (SLE) show potential new targets for therapy: (1) macrophage activation syndrome (MAS) often develops concomitantly with childhoodâonset SLE; (2) first data from a National Institutes of Health program to accelerate therapies for SLE have been released; and (3) mechanistic target of rapamycin (mTOR) activation contributes to the depletion and dysfunction of Treg cells in patients with lupus, which suggests that mTOR may become a therapeutic target in SLE.1-3
Scroll through the slides for the details of the studies and their clinical implications.
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A single-center study at The Hospital for Sick Children at the University of Toronto from 2002 to 2012 included 403 patients with childhoodâonset SLE who were followed up and who also received a diagnosis of MAS.1
A total of 38 patients (9%) with childhoodâonset SLE had MAS. More than two-thirds of the patients (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of corticosteroids, and time to disease damage were similar between those with and those without MAS.
Clinical implications: MAS commonly develops with childhood-onset SLE. The majority of the patients with MAS were successfully treated with corticosteroids with no MAS relapses. However, there was a higher risk of death associated with MAS compared to SLE without MAS.
The first datasets characterizing individual cells in SLE disease tissue have been released from the Accelerating Medicines Partnership for Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) phase I study. The AMP RA/SLE program is one of three AMP projects launched in 2014 as part of a public-private partnership to identify promising biological targets for potential therapeutics and to reduce the time and cost of development.2
This study used state-of-the-art technologies to analyze individual cells from the kidneys of patients with SLE from research cohorts whose clinical characteristics were well-studied. By focusing on single cells, researchers can tease out the contributions of specific pathways inside these cells that may play a role in disease, providing a new approach to understanding autoimmunity.
Plans are underway for a phase II, prospective, multi-center, longitudinal study of patients with SLE who have active renal disease and who require a biopsy.
Clinical implications: The newly released information holds clues for potential research targets that may lead to future treatment options. The data expand the search for genes, proteins, biological pathways, and other factors that influence SLE and have potential implications for precision medicine to identify differences in the pathways active in the tissue of different patients.
Activities of mTOR complexes 1 (mTORC1) and 2 (mTORC2) were examined by quantifying phosphorylation of translation initiation factor 4E–binding protein 1, S6 kinase, and Akt in patients with SLE relative to ageâ and sexâmatched female healthy controls.3
SLE Treg cells exhibited increased activities of mTORC1 and mTORC2. Autophagy, the expression of GATAâ3 and CTLAâ4, and the suppressor function of Treg cells were diminished. Interleukin-21 (ILâ21) blocked the development of Treg cells and stimulated mTOR, and also abrogated the autophagy, differentiation, and function of Treg cells.
Clinical implications: ILâ21 drives the mTOR axis via suppression of autophagy in SLE patients, leading to mTOR activation within Treg cells and the depletion and dysfunction of Treg cells. This is a pharmacologically targetable checkpoint of the deficient autophagy in these patients, stated the researchers, led by Hiroshi Kato of the State University of New York, Syracuse.